Department of Biochemistry and Molecular Pharmacology , University of Massachusetts Medical School , 364 Plantation Street , Worcester , Massachusetts 01605 , United States.
Program in Chemical Biology , University of Massachusetts Medical School , 364 Plantation Street , Worcester , Massachusetts 01605 , United States.
ACS Chem Biol. 2018 Apr 20;13(4):1057-1065. doi: 10.1021/acschembio.8b00053. Epub 2018 Mar 16.
Protein arginine deiminases (PADs) play an important role in the pathogenesis of various diseases, including rheumatoid arthritis, multiple sclerosis, lupus, ulcerative colitis, and breast cancer. Therefore, the development of PAD inhibitors has drawn significant research interest in recent years. Herein, we describe the development of the first photoswitchable PAD inhibitors. These compounds possess an azobenzene photoswitch to optically control PAD activity. Screening of a series of inhibitors structurally similar to BB-Cl-amidine afforded compounds 1 and 2 as the most promising candidates for the light-controlled inhibition of PAD2; the cis isomer of 1 is 10-fold more potent than its trans isomer, whereas the trans isomer of 2 is 45-fold more potent than the corresponding cis isomer. The altered inhibitory potency upon photoisomerization has been confirmed in a competitive activity-based protein profiling (ABPP) assay. Further investigations indicate that the trans isomer of 2 is an irreversible inhibitor, whereas the cis isomer acts as a competitive inhibitor. In cells, the trans isomer of compound 1 is completely inactive, whereas the cis isomer inhibits histone H3-citrullination in a dose-dependent manner. Taken together, 1 serves as the foundation for developing photopharmaceuticals that can be activated at the desired tissue, using light, to treat diseases where PAD activity is dysregulated.
蛋白质精氨酸脱亚氨酶（PADs）在多种疾病的发病机制中发挥着重要作用，包括类风湿性关节炎、多发性硬化症、狼疮、溃疡性结肠炎和乳腺癌。因此，近年来，PAD 抑制剂的开发引起了广泛的研究兴趣。在此，我们描述了第一种光可切换 PAD 抑制剂的开发。这些化合物具有一个偶氮苯光开关，可光学控制 PAD 活性。对一系列结构类似于 BB-Cl-脒的抑制剂进行筛选，得到了化合物 1 和 2，它们是光控抑制 PAD2 的最有前途的候选物；1 的顺式异构体比其反式异构体强 10 倍，而 2 的反式异构体比相应的顺式异构体强 45 倍。光异构化引起的抑制效力变化已在竞争性基于活性的蛋白质谱分析（ABPP）测定中得到证实。进一步的研究表明，2 的反式异构体是一种不可逆抑制剂，而顺式异构体则作为竞争性抑制剂起作用。在细胞中，化合物 1 的反式异构体完全没有活性，而顺式异构体则以剂量依赖的方式抑制组蛋白 H3 瓜氨酸化。综上所述，1 为开发光药物奠定了基础，这些光药物可以在需要的组织中用光激活，以治疗 PAD 活性失调的疾病。
